© 1995 American Heart Association, Inc.
Articles |
Upregulation of Cardiac Angiotensin II AT1 Receptors in Congenital Cardiomyopathic Hamsters
From the Department of Pharmacology (C.L., Y.M., S.M.), Faculty of Medicine, Université de Montréal (Canada), and Centre de Recherche (S.M.), Hôtel-Dieu de Montréal (Canada).
Correspondence to Chantal Lambert, BPharm., PhD, CP 6128, Succursale Centre-Ville, Montréal, H3C 3J7, Canada.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Abstract Angiotensin II (Ang II) is a growth factor that stimulates protein synthesis and induces cellular hypertrophy in cardiac myocytes. To gain insight into the role of Ang II in cardiac hypertrophy, we examined the expression and subtype distribution of Ang II receptors in the ventricles of embryonic and of 25- to 350-day-old inbred control and cardiomyopathic (CHF 146) hamsters. Studies were also performed with heterozygous (cardiomyopathicxcontrol) animals. Compared with the control hamsters, cardiomyopathic hamsters presented decreased body weights and increased ratios of ventricular weight to body weight in every adult group studied. Typical histological lesions appeared in the left ventricle of cardiomyopathic animals around 70 to 75 days, and their severity increased with time. Radioligand binding studies with cardiac ventricular membranes indicated that iodinated [Sar1,Ile8]Ang II (sarile) binds to a homogeneous population of sites in membranes derived from adult normal and cardiomyopathic animals. Competition curves using specific receptor subtype antagonists revealed that 125I-sarile binding sites were exclusively of the AT1 subtype in both groups of animals. Importantly, the density of AT1 receptors was found to be significantly increased (90% augmentation at 70 to 75 days) in the ventricles of cardiomyopathic hamsters. This augmented expression was observed in all adult groups and was already present at 25 days, when no histological lesions were visible. The affinity of the receptor for losartan did not vary significantly between adult normal and cardiomyopathic animals (mean Kd, 19.6 and 16.7 nmol/L, respectively). No significant differences were observed in the total expression of Ang II receptors and in the proportion of AT1 and AT2 subtypes between the two groups of embryonic hearts. Heterozygous animals expressed an intermediate level of AT1 receptor binding activity in their ventricles. Together, these results suggest that Ang II acting through the AT1 receptor may play a critical role in the development and/or maintenance of cardiac hypertrophy.
Key Words: cardiomyopathic hamsters • angiotensin receptors • losartan • hypertrophy • heart
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The renin-angiotensin system plays a major role in the regulation of normal cardiac function and in the pathophysiology of a number of disease states. The direct actions of angiotensin II (Ang II) on the heart include effects on contractility, heart rate, arrhythmogenesis, and myocardial function.1 2 3 Besides these acute hemodynamic effects, accumulating evidence indicates that Ang II also exerts long-term effects on cardiac muscle growth and likely contributes to the development of cardiac hypertrophy.1 4 In vivo studies have shown that the chronic infusion of Ang II to adult rats increases left ventricular mass even in the absence of pressor activity.5 6 In newborn pigs, the administration of either the angiotensin-converting enzyme inhibitor enalapril or the AT1-selective antagonist losartan interfered with the rapid growth of neonatal hearts.7 Furthermore, treatment with angiotensin-converting enzyme inhibitors was shown to prevent or reverse myocardial hypertrophy in rat models of pressure-overload hypertrophy8 9 and in spontaneously hypertensive rats.10 11 Similar findings were reported in hypertensive patients.12 13 Consistent with the notion that it acts as a growth factor for the myocardium, Ang II was clearly shown to increase protein synthesis and to induce cellular hypertrophy in cultured cardiomyocytes.14 15 16
The growth-promoting action of Ang II might be mediated by circulating or locally produced hormone. As in several other organs and tissues, the heart also appears to possess its own local renin-angiotensin system, which may function in an autocrine or paracrine manner.1 2 17 Thus, all of the components required for local production of Ang II, angiotensinogen,18 19 renin,19 20 and angiotensin-converting enzyme21 have been identified in the heart. Moreover, the presence of Ang II immunoreactivity has been detected in cultured rat cardiac myocytes and fibroblasts and in the culture medium of stretch-stimulated cells.22 23
Ang II exerts its physiological actions by interacting with two pharmacologically distinct subtypes of receptors, identified as AT1 and AT2.24 Pharmacological studies have revealed that the AT1 subtype is responsible for the all known biological actions of the hormone, including the growth-promoting effects.24 25 In cardiac tissues, Ang II receptors have been localized to the myocardium, coronary vessels, sympathetic nerves, and conduction system.1 2 With the development of selective receptor antagonists, it has been possible to examine the distribution pattern of Ang II receptor subtypes in the heart by using radioligand binding assays or in situ autoradiography. The AT1 and AT2 subtypes were found to be expressed in nearly equal ratios in rat26 27 and rabbit28 hearts, whereas monkey29 and bovine30 tissues contain twice as many AT1 receptors. The human ventricular myocardium predominantly expresses the AT2 receptor subtype.30 Interestingly, recent studies have demonstrated that cardiac AT1 receptor expression is increased in rat models of cardiac hypertrophy27 31 and after myocardial infarction.32 33
The aim of the present study was to evaluate the relation between the development of cardiac hypertrophy and the expression of Ang II receptors by use of cardiomyopathic Syrian hamsters. These animals develop a hereditary progressive cardiomyopathy resembling the hypertrophic cardiomyopathy observed in humans.34 It is characterized by spontaneous focal necrotic lesions detected in the heart after the first months of life that are followed by cardiac hypertrophy during late months and ultimate death as a consequence of heart failure.35 36 37
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Materials
Losartan (DuP 753) was kindly supplied by Dr Ronald D. Smith from Du Pont Merck Pharmaceutical Co; PD 123319, by Dr Joan Keiser from Parke-Davis. [Sar1,Ile8]Ang II (sarile) was purchased from Hukabel Scientific and iodinated in our laboratory. The protease inhibitors phenylmethylsulfonyl fluoride (PMSF), leupeptin, and pepstatin A were obtained from Sigma Chemical Co; Iodo-Beads, from Pierce; and sodium iodide I-125, from Amersham.
Animals
Male Syrian cardiomyopathic (CHF 146) and inbred
control (CHF 148) hamsters (25 to 30, 70 to 75, 125 to 150, 225 to 250,
and 325 to 350 days old) and 14- to 16-day-pregnant
cardiomyopathic and inbred control hamsters were
purchased from the Canadian Hybrid Farms (Halls Harbour, Nova Scotia,
Canada). Heterozygous male hamsters were bred by female
cardiomyopathicxmale control and female controlxmale
cardiomyopathic hamster matings. All procedures for
animal experimentation conformed to the guidelines of the Canadian
Council for Animal Care and were monitored by an institutional animal
care committee.
Iodination of Sarile
Sarile was radioiodinated by a solid-phase
method using Iodo-Beads as the oxidizing agent.38 Briefly,
10 nmol of sarile was incubated at 4°C for 20 minutes with 1 mCi of
sodium iodide I-125 and two Iodo-Beads in 100 µL of 0.5 mol/L
potassium phosphate buffer (pH 7.0). The monoiodinated
peptide was purified by high-performance liquid
chromatography on a reverse-phase Vydac
C18 column. Elution was achieved at a flow rate of 1 mL/min
by using a 80-minute linear gradient of 15% to 55% acetonitrile in
0.1% trifluoroacetic acid. Fractions of 1.0 mL were collected and
counted for radioactivity. This method yielded typical
125I-sarile specific activities of 1700 to 2100
Ci/mmol.
Cardiac Membrane Preparation
The animals were anesthetized with thiopental (50 mg/kg
IP). Adult and embryonic (days 14 to 16 of gestation) hearts were
quickly removed and allowed to beat in ice-cold PBS. After they
were washed, the left and right ventricles were dissected, weighed, and
minced with scissors, and membranes were prepared as previously
described by Meloche et al39 with the following
modifications: Pooled adult (n=4 to 6) and embryonic (n=20 to 30)
hearts were homogenized in 20 mmol/L
NaHCO3, 10 mmol/L EDTA, 10-4 mol/L
PMSF, 10-6 mol/L leupeptin, and 10-6 mol/L
pepstatin A. The resulting high-spin membrane pellet was washed
once with 20 mmol/L NaHCO3, 1 mmol/L EDTA,
10-4 mol/L PMSF, 10-6 mol/L leupeptin, and
10-7 mol/L pepstatin A. The membranes were frozen in
liquid nitrogen and stored at -80°C until used. Freezing and thawing
of the membranes did not result in any loss of receptor binding
activity (data not shown). The protein concentration was assayed by the
colorimetric method of Lowry et al.40
Receptor Binding Assay
Cardiac ventricular membranes (250 µg) were
incubated with 0.2 nmol/L 125I-sarile and varying
concentrations of competing agents for 60 minutes at 25°C in a total
volume of 250 µL of 50 mmol/L Tris-HCl (pH 7.4), 150 mmol/L NaCl, 0.1
mmol/L EDTA, 1 mmol/L MgCl2, and 0.1%
heat-inactivated BSA. Bound 125I-sarile was
separated from free ligand by rapid filtration through GF/B filters
presoaked with 0.2% BSA, followed by washing with 50 mmol/L Tris-HCl
(pH 7.4) and 150 mmol/L NaCl. The radioactivity present in the
filters was counted in a Cobra Auto-Gamma (Packard) counter with 74%
efficiency. Averages of duplicate determinations of bound
125I-sarile were used for data analysis.
Competition binding curves were analyzed by nonlinear
least-squares curve fitting using the SCAFIT computer
program.41 Equilibrium binding constants are reported as
Kd, and receptor concentrations are
expressed as femtomoles per milligram of protein. For in utero and
heterozygous animals, total binding was measured by incubating
ventricular membranes (250 µg) with 0.2 nmol/L
125I-sarile in the absence or presence of the
AT1-selective antagonist losartan
(10-5 mol/L) or the AT2-selective
antagonist PD123319 (3x10-6 mol/L).
Histology
Left ventricular myocardial free walls were fixed in
10% neutral formalin. Four-micron transverse sections were then
stained with hematoxylin-phloxin-saffron before examination for
necrotic lesions.42 Calcification was examined by using
the von Kossa calcium technique.43
Statistics
Data are presented as mean±SEM. Results were evaluated
by unpaired Student’s t tests or one-way ANOVA and
Bonferroni t tests. The critical level of significance was
set at P
.05.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The cardiomyopathic hamster is a particularly interesting model of experimental cardiomyopathy for two main reasons: (1) the slow progression of the disease allows the cardiac system to be studied at different steps in the development of the pathology, and (2) the abnormalities at each stage of the disease are reproducible and predictable.44 Animals of 25 to 30 (prenecrotic phase), 70 to 75 (necrotic phase), 125 to 150 (healing stage with hypertrophy and dilatation), 225 to 250, and 325 to 350 days of age (progressing dilatation and terminal heart failure) were used in this study.36 37 45 Compared with the inbred control animals, the cardiomyopathic hamsters presented, at all stages, significantly decreased body weights (Fig 1A
). This observation is consistent
with the findings of Hunter et al37 and
Rossner46 and might be explained by the fact that the
degree of the progressive loss of the skeletal muscle and adipose
tissue exceeded the degree of the generalized fluid retention caused by
heart failure.47 As already reported by
others,47 48 despite the decrease in body weight, cardiac
hypertrophy clearly developed in the
cardiomyopathic hamsters, as indicated by the
significantly augmented ventricular
weight–to–body weight ratios (Fig 1B).
|
The progression of lesion formation in the cardiac muscle of the CHF
146 strain of cardiomyopathic hamsters has been
described by Hunter et al.37 These authors reported that
the development of lesions in these specific animals appears to be
similar to that seen in other strains, such as BIO 14.6 and UM-X7.1,
with the first lesions appearing in the left ventricle at 60 days of
age. In the present study, no histological lesions
were observed in the inbred control animals at any age or in the
cardiomyopathic hamsters at 25 to 30 days of age.
However, focal necrotic changes and calcium deposition were already
observed in the left ventricular wall of 70- to
75-day-old cardiomyopathic animals (Fig 2). These typical lesions were observed with an increasing
density over time, and a constant worsening of the disease was noted in
aging animals.
|
It is well established that the renin-angiotensin
system is activated in human heart failure.49 It
has also been demonstrated that the cardiomyopathic
hamsters, compared with normal hamsters, display an activated
renin-angiotensin system that is characterized by
higher plasma and left ventricular Ang II
concentrations47 as well as by higher
ventricular angiotensin-converting enzyme
activity.36 Furthermore, it has been reported that
angiotensin-converting enzyme inhibitors,
such as quinapril, cilasapril, and captopril, prevent the progression
of left ventricular failure and increase the median
probability of survival of the cardiomyopathic
animals.36 47 50 These data suggest that the
cardiomyopathic hamsters have a
renin-angiotensin profile similar to that in humans and
therefore provide a suitable model for investigating the role of this
system in heart failure. To determine whether changes at the level of
Ang II receptors might be associated with the development of cardiac
hypertrophy, we examined the expression and subtype
distribution of Ang II receptors in the ventricles of normal and
cardiomyopathic hamsters of 25 to 350 days of age. Fig 3 shows the characteristics of 125I-sarile
binding to cardiac ventricular membranes of 125-day-old
hamsters in competition experiments. Computer analysis of
binding data indicated that 125I-sarile binds to a
homogeneous population of sites in membranes derived from
normal and cardiomyopathic animals, with dissociation
constants of 0.76 and 0.67 nmol/L, respectively. Competition curves
with the selective antagonists losartan and PD
123319 revealed that losartan potently and completely displaced
125I-sarile binding in both groups of animals, whereas no
significant binding of PD 123319 was detected. These results
demonstrate that in contrast to other species such as rat, rabbit, or
monkey, the hamster ventricles express only the AT1 subtype
of Ang II receptors. The lack of expression of AT2
receptors was observed in normal and cardiomyopathic
hamsters of every adult group (data not shown).
|
Competition binding studies with losartan were performed to
quantitatively evaluate the binding characteristics of the cardiac
ventricular AT1 receptor in both groups of
hamsters. Interestingly, we found that the density of AT1
receptors was significantly increased in the ventricles of
cardiomyopathic animals, with a maximum augmentation of
90% observed at 70 to 75 days of age (Fig 4). The
expression of the AT1 receptor was observed to increase in
every age group studied and was already present in
cardiomyopathic hamsters aged 25 to 30 days, when no
histological lesions were observed. The affinity of
losartan for the AT1 receptor did not vary
significantly between normal (Kd,
19.6±0.9 nmol/L; n=15) and cardiomyopathic
(Kd, 16.7±0.7 nmol/L; n=15) animals or
between the different age groups. Our present results are in
agreement with recent reports showing that the establishment of cardiac
hypertrophy in spontaneously hypertensive and renovascular
hypertensive rats or in rats after coarctation of the abdominal aorta
is associated with a significant increase in the expression of
AT1 receptors in the ventricles.27 31 In their
study, Suzuki et al27 reported that expression of both the
AT1A and AT2 receptor subtypes, which is nearly
equal in their experimental model, is upregulated during the
development of myocardial hypertrophy. However, treatment
of renovascular hypertensive animals with an AT1
antagonist completely reversed the index of cardiac
hypertrophy to the control level, whereas the
AT2 antagonist had no effect. In a related
study, Meggs et al32 showed that the density of
AT1, but not AT2 receptors is augmented
in isolated ventricular myocytes after acute myocardial
infarction. Similar findings were reported by Nio et al,33
although these authors demonstrated that myocardial infarction also
causes an increase in the gene transcription and protein expression of
the AT2 receptor. Taken together, these observations
strongly suggest that Ang II acting via the AT1 receptor
may play a pivotal role in the reactive hypertrophy of the
heart.
|
Numerous investigators have reported varying degrees of change in 
-
as well as in ß-adrenergic receptors in the hearts of
cardiomyopathic hamsters from different
strains.51 It has also been demonstrated that the
synthesis and secretion of the atrial natriuretic peptide
are increased in the ventricles of cardiomyopathic
hamsters during moderate to severe heart failure.52 53
However, to the best of our knowledge, the present study is the
first to report that the development of cardiac hypertrophy
in the cardiomyopathic animals is associated with an
upregulation of Ang II receptors and more specifically of the
AT1 subtype.
Little is known on the molecular basis about the increased expression
of AT1 receptors in experimental models of cardiac
hypertrophy. Since the upregulation of
ventricular AT1 receptor was observed at a very
early stage in cardiomyopathic hamsters, before the
apparition of histological lesions, we verified whether
the expression of the receptor was already elevated in embryonic
hearts. For these experiments, total Ang II binding activity was
determined in ventricular membranes prepared from in utero
animals (days 14 to 16 of gestation). In contrast to the results
obtained in adult hearts, the AT2 receptor subtype was
found to represent a significant proportion (
45%) of the
total 125I-sarile binding activity (Fig 5).
However, no differences were observed between control and
cardiomyopathic hamsters in the total expression of Ang
II receptors and in the proportion of AT1 and
AT2 subtypes (Fig 5). To determine whether AT1
receptor density might be genetically regulated, we next examined the
expression of the receptor in cardiac ventricular membranes
from heterozygous (cardiomyopathicxcontrol) hamster
strains. As shown in Fig 6, the AT1 receptor
binding activity in the ventricles of heterozygous animals was found to
be midway between that of control and cardiomyopathic
animals. These findings strongly suggest that the abnormal expression
of the AT1 receptor in the heart of
cardiomyopathic hamsters is directly regulated at the
genetic level. Additional genetic studies will be required to establish
whether the AT1 receptor gene itself is abnormal in these
animals.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The exact mechanisms implicated in the pathogenesis of the cardiomyopathy in the hamster model are not well understood. Nevertheless, considerable evidence points to a critical role for circulating and for cardiac Ang II in this process. First, Ang II induces hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts in vitro.14 15 16 54 Second, plasma and cardiac Ang II levels are significantly higher in cardiomyopathic than in control hamsters.47 55 Third, the AT1 receptor is upregulated in the ventricles of cardiomyopathic animals (the present study). Fourth, chronic administration of angiotensin-converting enzyme inhibitors has a beneficial effect on parameters such as cardiac structure, heart performance, and survival rate in cardiomyopathic animals.36 44 47 56 57 58 59 Finally, perhaps the most convincing evidence is the demonstration that chronic administration of the Ang II AT1 receptor antagonist TCV-116 significantly improves cardiac contractility in cardiomyopathic hamsters.55
In summary, we have demonstrated that the Ang II AT1 receptor is upregulated in the ventricles of cardiomyopathic hamsters. Since the increased expression of AT1 receptors was already present at a stage when no histological lesions were detected and since heterozygous animals express intermediate density, our results suggest that Ang II acting via the AT1 receptor may play a role in the genesis and/or the maintenance of the cardiac hypertrophy in the hamster.
|
Acknowledgments |
|---|
This study was supported by grants to Drs Lambert (MA-11527) and Meloche (MT-12150) from the Medical Research Council of Canada. Dr Lambert holds a scholarship from the Heart and Stroke Foundation of Canada; Y. Massillon, a studentship from the Medical Research Council of Canada; and Dr Meloche, a scholarship from the Medical Research Council of Canada. The authors wish to thank Marie-France Legault for her excellent technical assistance and Elisabeth Pérès for the artwork. We are also grateful to Dr André DeLéan and Normand McNicoll for giving us access to their iodination and computer facilities.
Received April 6, 1995; accepted July 5, 1995.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Baker KM, Booz GW, Dostal DE. Cardiac actions of angiotensin II: role of an intracardiac renin-angiotensin system. Annu Rev Physiol.. 1992;54:227-241. [Medline] [Order article via Infotrieve]
2. Dostal DE, Baker KM. Evidence for a role of an intracardiac renin-angiotensin system in normal and failing hearts. Trends Cardiovasc Med.. 1993;3:67-74.
3. Freed MI, Ilson BE, Shusterman NH, Jorkasky DK. Therapeutic applications of angiotensin II antagonists. In: Ruffolo RR, ed. Angiotensin II Receptors. Boca Raton, Fla: CRC Press: 1994:121-154.
4. Schelling P, Fischer H, Ganten D. Angiotensin and cell growth: a link to cardiovascular hypertrophy? J Hypertens.. 1990;9:3-15.
5. Khairallah PA, Kanabus J. Angiotensin and myocardial protein synthesis. In: Tarazi RC, Dunbar JB, eds. Cardiac Hypertrophy in Hypertension. New York, NY: Raven Press Publishers: 1983:337-347.
6. Dostal DE, Baker KM. Angiotensin II stimulation of left ventricular hypertrophy in adult rat heart: mediation by the AT1 receptor. Am J Hypertens.. 1992;5:276-280. [Medline] [Order article via Infotrieve]
7. Beinlich CJ, White GJ, Baker WM, Morgan HE. Angiotensin II and left ventricular growth in newborn pig heart. J Mol Cell Cardiol.. 1991;23:1031-1038. [Medline] [Order article via Infotrieve]
8. Linz W, Schoelkens BA, Ganten D. Converting enzyme inhibition specifically prevents the development and induces the regression of cardiac hypertrophy in rats. Clin Exp Hypertens.. 1989;11:1325-1350.
9.
Baker KM, Cherin MI, Wixon SK, Aceto JF. Renin
angiotensin system involvement in pressure-overload
cardiac hypertrophy in rats. Am J
Physiol.. 1990;259:H324-H332.
10.
Pfeffer JM, Pfeffer MA, Mirsky L, Braunwald E.
Regression of left ventricular
hypertrophy and prevention of left ventricular
dysfunction by captopril in the spontaneously hypertensive rat.
Proc Natl Acad Sci U S A.. 1982;79:3310-3314.
11. Clozel JP, Kuhn H, Heft F. Effects of chronic ACE inhibition on cardiac hypertrophy and coronary vascular reserve in spontaneously hypertensive rats with developed hypertension. J Hypertens.. 1989;7:267-275. [Medline] [Order article via Infotrieve]
12. Dunn FG, Digman W, Ventura HO, Messerli FH, Kobrin I, Frohlich ED. Enalapril improves systemic and renal hemodynamics and allows regression of left ventricular mass in essential hypertension. Am J Cardiol.. 1984;53:105-108. [Medline] [Order article via Infotrieve]
13. Liebson PR. Clinical studies of drug reversal of hypertensive left ventricular hypertrophy. Am J Hypertens.. 1990;3:512-517. [Medline] [Order article via Infotrieve]
14.
Baker KM, Aceto JF. Angiotensin II
stimulation of protein synthesis and cell growth in chick heart
cells. Am J Physiol.. 1990;259:H610-H618.
15.
Sadoshima J, Izumo S. Molecular characterization
of angiotensin II–induced hypertrophy of
cardiac myocytes and hyperplasia of cardiac fibroblasts: critical role
of the AT1 receptor subtype. Circ Res.. 1993;73:413-423.
16.
Miyata S, Haneda T. Hypertrophic growth of
cultured neonatal rat heart cells mediated by type 1
angiotensin II receptor. Am J Physiol.. 1994;266:H2443-H2451.
17. Paul M, Bachmann J, Ganten D. The tissue renin-angiotensin systems in cardiovascular disease. Trends Cardiovasc Med.. 1992;2:94-99.
18. Campbell DJ, Habener JF. Angiotensinogen gene is expressed and differentially regulated in multiple tissues of the rat. J Clin Invest.. 1986;78:31-39.
19.
Dostal DE, Rothblum KN, Chernin MI, Cooper GR, Baker
KM. Intracardiac detection of angiotensinogen and
renin: a localized renin-angiotensin system in neonatal
rat heart. Am J Physiol.. 1992;263:C838-C850.
20.
Dzau VJ, Ellisor KE, Brody T, Ingelfinger J, Pratt RE.
A comparative study of the distributions of renin and
angiotensinogen messenger ribonucleic acids in rat and
mouse tissues. Endocrinology.. 1987;120:2334-2338.
21. Schunkert H, Dzau VJ, Tang SS, Hirsch AT, Apstein CS, Lorell BH. Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy: effects on coronary resistance, contractility, and relaxation. J Clin Invest.. 1990;86:1913-1920.
22. Dostal DE, Rothblum KN, Conrad KM, Cooper GR, Baker KM. Detection of angiotensin I and II in cultured rat cardiac myocytes and fibroblasts. Am J Physiol.. 1992;263:851-863.
23. Sadoshima JI, Xu Y, Slater HS, Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell.. 1993;75:977-984. [Medline] [Order article via Infotrieve]
24. Timmermans PBMWM, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JAM, Smith RD. Angiotensin II receptors and angiotensin II receptor antagonist. Pharmacol Rev.. 1993;45:205-251. [Medline] [Order article via Infotrieve]
25. Smith RD, Chiu AT, Wong PC, Herblin WF, Timmermans PBMWM. Pharmacology of non peptide angiotensin II receptor antagonist. Annu Rev Pharmacol Toxicol.. 1992;32:135-165. [Medline] [Order article via Infotrieve]
26.
Sechi LA, Griffin CA, Grady EF, Kalinyack JE,
Schambelan M. Characterization of angiotensin II
receptor subtypes in rat heart. Circ Res.. 1992;71:1482-1489.
27.
Suzuki J, Matsubara H, Urakami M, Inada M. Rat
angiotensin II (type 1A) receptor mRNA regulation and
subtype expression in myocardial growth and
hypertrophy. Circ Res.. 1993;73:439-447.
28. Rogg H, Schmid A, de Gasparo M. Identification and characterization of angiotensin II receptor subtypes in rabbit ventricular myocardium. Biochem Biophys Res Commun.. 1990;173:416-422. [Medline] [Order article via Infotrieve]
29. Chang RSL, Lotti VJ. Angiotensin receptor subtypes in rat, rabbit and monkey tissues: relative distribution and species dependency. Life Sci.. 1991;49:1485-1490. [Medline] [Order article via Infotrieve]
30.
Nozawa Y, Haruro A, Oda N, Yamasaki Y, Matsuura N,
Yamada S, Inabe K, Kimura R, Suzuki H, Hoshino T.
Angiotensin II receptor subtypes in bovine and human
ventricular myocardium. J
Pharmacol Exp Ther.. 1994;270:566-571.
31.
Everett AD, Tufro-McReddie A, Fischer A, Gomez RA.
Angiotensin receptor regulates cardiac
hypertrophy and transforming growth factor-ß1
expression. Hypertension.. 1994;23:587-592.
32.
Meggs LG, Coupet J, Huang H, Cheng W, Li P, Capasso JM,
Homcy CJ, Anversa P. Regulation of angiotensin II
receptors on ventricular myocytes after myocardial
infarction in rats. Circ Res.. 1993;72:1149-1162.
33. Nio Y, Matsubata H, Morasawa S, Kanasaki M, Inada M. Regulation of gene transcription of angiotensin II receptor subtypes in myocardial infarction. J Clin Invest.. 1995;95:46-54.
34. Malhotra A. Contractile and regulatory proteins in hamster cardiomyopathy. In: Nagano M, Takeda N, Dhalla NS, eds. The Cardiomyopathic Heart. New York, NY: Raven Press Publishers: 1994:31-39.
35. Ver Donck L, Verellen G, Geerts H, Olbrich HG, Mutschler E, Borgers M. Altered contractile behavior of cardiomyocytes from cardiomyopathic hamsters. In: Nagano M, Takeda N, Dhalla NS, eds. The Cardiomyopathic Heart. New York, NY: Raven Press Publishers; 1994:49-55.
36.
Haleen SJ, Weishaar RE, Overhiser RW, Bousley RF,
Keiser JA, Rapundalo SR, Taylor DG. Effects of quinapril, a new
angiotensin converting enzyme inhibitor, on
left ventricular failure and survival in the
cardiomyopathic hamster: hemodynamic,
morphological, and biochemical correlates. Circ Res.. 1991;68:1302-1312.
37. Hunter EG, Hugues V, White J. Cardiomyopathic hamsters, CHF 146 and CHF 147: a preliminary study. Can J Physiol Pharmacol.. 1984;62:1423-1428. [Medline] [Order article via Infotrieve]
38. Markwell MAK. A new solid-state reagent to iodinate proteins. Anal Biochem.. 1982;125:427-432. [Medline] [Order article via Infotrieve]
39. Meloche S, Ong H, Cantin M, DeLéan A. Molecular characterization of the solubilized atrial natriuretic factor receptor from bovine adrenal zona glomerulosa. Mol Pharmacol.. 1986;30:537-543. [Abstract]
40.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ.
Protein measurement with folin phenol reagent.
J Biol Chem.. 1951;193:265-275.
41. DeLéan A, Hancock AA, Lefkowitz RJ. Validation and statistical analysis of a computer modeling method for quantitative analysis of radioligand binding data for mixtures of pharmacological receptor subtypes. Mol Pharmacol.. 1982;21:5-16. [Abstract]
42. Luna LG. Routine staining procedures. In: Luna LG, ed. Manual of Histologic Staining Methods of the Armed Forces Institute of Pathology. New York, NY: McGraw-Hill Publishing Co; 1968:32-46. American Registry of Pathology.
43. Luna LG. Methods for pigments and minerals. In: Luna LG, ed. Manual of Histologic Staining Methods of the Armed Forces Institute of Pathology. New York, NY: McGraw-Hill Publishing Co; 1968:174-188. American Registry of Pathology.
44. Chemla D, Scalbert E, Desché P, Lecarpentier Y. La cardiomyopathie du hamster Syrien: aspects physiopathologiques et thérapeutiques. Arch Mal Coeur.. 1991;84:85-87.
45. Wikman-Coffelt J, Sievers R, Parmley WW, Jasmin G. Verapamil preserves adeninenucleotide pool in cardiomyopathic Syrian hamster. Am J Physiol.. 1986;250:H22-H28.
46.
Rossner KL. Calcium current in congestive heart
failure of hamster cardiomyopathy. Am
J Physiol.. 1991;260:H1179-H1186.
47. Nakamura F, Nagano M, Kobayashi R, Higaki J, Mikami H, Kawaguchi N, Onishi S, Ogihara T. Effects of an angiotensin-converting enzyme inhibitor, cilazapril, on congestive heart failure in cardiomyopathic hamsters. In: Nagano M, Takeda N, Dhalla NS, eds. The Cardiomyopathic Heart. New York, NY: Raven Press Publishers; 1994:145-156.
48.
Hirakata H, Fouad-Tarazi FM, Bumpus FM, Khosla M, Healy
B, Husain A, Urata H, Kumagai H. Angiotensins and
the failing heart: enhanced positive inotropic response to
angiotensin I in cardiomyopathic hamster
heart in the presence of captopril. Circ Res.. 1990;66:891-899.
49. Hirsch A, Pinto YM, Schunkert H, Dzau VJ. Potential role of the tissue renin-angiotensin system in the pathophysiology of congestive heart failure. Am J Cardiol.. 1990;66:22D-32D. [Medline] [Order article via Infotrieve]
50. Kato M, Yang J, Iwai T, Tanamura A, Takeda N, Nagano M. Effects of angiotensin converting enzyme inhibitors and prostaglandin E1 derivatives on the cardiomyopathic hamster. In: Nagano M, Takeda N, Dhalla NS, eds. The Cardiomyopathic Heart. New York, NY: Raven Press Publishers; 1994:157-164.
51. Sethi R, Panagia V, Dhalla KS, Beamish RE, Jasmin G, Dhalla NS. Status of ß-adrenergic mechanisms during the development of congestive heart failure in cardiomyopathic hamsters (UM-X7.1). In: Nagano M, Takeda N, Dhalla NS, eds. The Cardiomyopathic Heart. New York, NY: Raven Press Publishers; 1994:73-86.
52.
Thibault G, Nemer M, Drouin J, Lavigne JP, Ding J,
Charbonneau C, Garcia R, Genest J, Jasmin G, Sole M, Cantin M.
Ventricles as a major site of atrial natriuretic
factor synthesis and release in cardiomyopathic
hamsters with heart failure. Circ Res.. 1989;65:71-82.
53.
Franch HA, Dixon RAF, Blaine EH, Siegl PKS.
Ventricular atrial natriuretic factor in
the cardiomyopathic hamster model of congestive heart
failure. Circ Res.. 1988;62:31-36.
54.
Schorb W, Booz GW, Dostal DE, Conrad KM, Chang KC,
Baker KM. Angiotensin II is mitogenic in
neonatal rat cardiac fibroblasts. Circ Res.. 1993;72:1245-1254.
55.
Nakamura F, Nagano M, Kobayashi R, Higaki J, Mikami H,
Kawaguchi N, Onishi S, Ogihara T. Chronic administration of
angiotensin II receptor antagonist, TCV-116, in
cardiomyopathic hamsters. Am J
Physiol.. 1994;267:H2297-H2304.
56. Kato M, Takeda N, Takeda A, Ohkubo T, Nagai M, Nagano M. Inhibitory effects of captopril on the onset of cardiomyopathy in cardiomyopathic hamsters. In: Korecky B, Dhalla NS, eds. Subcellular Basis of Contractile Failure. Norwell, Mass: Kluwer Academic Publishers; 1990:193-208.
57. Metz A, Haleen S, Brucchieri S, Davis L, LaDouceur D, Jaworski J, Keiser J, Gough A. Effects of ACE inhibition on development of myocardial lesions in the cardiomyopathic (CM) hamster. FASEB J.. 1993;7:A111. Abstract.
58. Araki T, Shimizu M, Sugihara N, Yoshio H, Ino H, Takeda R. Effect of angiotensin-converting enzyme inhibitor on myocardial collagen metabolism in cardiomyopathic hamsters. In: Nagano M, Takeda N, Dhalla NS, eds. The Cardiomyopathic Heart. New York, NY: Raven Press Publishers; 1994:137-143.
59. Kato M, Takeda N, Yang J, Nagano M. The effects of angiotensin converting enzyme inhibitors and the role of the renin-angiotensin-aldosterone system in J-2-N cardiomyopathic hamsters. Jpn Circ J.. 1992;56:46-51.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  D. M. Browe and C. M. Baumgarten Angiotensin II (AT1) Receptors and NADPH Oxidase Regulate Cl- Current Elicited by {beta}1 Integrin Stretch in Rabbit Ventricular Myocytes J. Gen. Physiol., August 30, 2004; 124(3): 273 - 287. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Schultz, X. Su, C.-C. Wei, S. P. Bishop, P. Powell, G. H. Hankes, A. R. Dillon, P. Rynders, F. G. Spinale, G. Walcott, et al. Downregulation of ANG II receptor is associated with compensated pressure-overload hypertrophy in the young dog Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H749 - H756. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Rouleau, G. Kapuku, S. Pelletier, H. Gosselin, A. Adam, C. Gagnon, C. Lambert, and S. Meloche Cardioprotective Effects of Ramipril and Losartan in Right Ventricular Pressure Overload in the Rabbit: Importance of Kinins and Influence on Angiotensin II Type 1 Receptor Signaling Pathway Circulation, August 21, 2001; 104(8): 939 - 944. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Ozono, T. Matsumoto, T. Shingu, T. Oshima, Y. Teranishi, M. Kambe, H. Matsuura, G. Kajiyama, Z.-Q. Wang, A. F. Moore, et al. Expression and localization of angiotensin subtype receptor proteins in the hypertensive rat heart Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2000; 278(3): R781 - R789. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. R. Bastien, A.-V. Juneau, J. Ouellette, and C. Lambert Chronic AT1 receptor blockade and angiotensin-converting enzyme (ACE) inhibition in (CHF 146) cardiomyopathic hamsters: effects on cardiac hypertrophy and survival Cardiovasc Res, July 1, 1999; 43(1): 77 - 85. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Matsubara Pathophysiological Role of Angiotensin II Type 2 Receptor in Cardiovascular and Renal Diseases Circ. Res., December 14, 1998; 83(12): 1182 - 1191. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ikezaki, H. Onyuksel, and I. Rubinstein Liposomal VIP attenuates phenylephrine- and ANG II-induced vasoconstriction in vivo Am J Physiol Regulatory Integrative Comp Physiol, August 1, 1998; 275(2): R588 - R595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ohkubo, H. Matsubara, Y. Nozawa, Y. Mori, S. Murasawa, K. Kijima, K. Maruyama, H. Masaki, Y. Tsutumi, Y. Shibazaki, et al. Angiotensin Type 2 Receptors Are Reexpressed by Cardiac Fibroblasts From Failing Myopathic Hamster Hearts and Inhibit Cell Growth and Fibrillar Collagen Metabolism Circulation, December 2, 1997; 96(11): 3954 - 3962. [Abstract] [Full Text]
|
|
|
|
 |
|
 E. Giasson, M. J. Servant, and S. Meloche Cyclic AMP-mediated Inhibition of Angiotensin II-induced Protein Synthesis Is Associated with Suppression of Tyrosine Phosphorylation Signaling in Vascular Smooth Muscle Cells J. Biol. Chem., October 24, 1997; 272(43): 26879 - 26886. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Regitz-Zagrosek, J. Fielitz, R Dreysse, A. G Hildebrandt, and E. Fleck Angiotensin receptor type 1 mRNA in human right ventricular endomyocardial biopsies: downregulation in heart failure Cardiovasc Res, July 1, 1997; 35(1): 99 - 105. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||